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Abstract: Persons with Down syndrome show an altered immune response and an increased susceptibility to Alzheimer''s disease. In a prospective study, we examined whether the plasma neopterin level, a marker for cell-mediated immune activation and inflammation, is associated with an increased risk of dementia in persons with Down syndrome. Plasma concentrations of neopterin were determined in a population-based study of 394 persons with Down syndrome, who were screened annually for dementia. We used Cox proportional hazards model to determine risk of dementia. Demented persons with Down syndrome have a significantly (p =0.05) higher plasma neopterin concentration than the non-demented. In the non-demented without autoimmune disorders, in those with a plasma level of neopterin above median, the risk to develop dementia increased to 1.83 (95% confidence interval: 1.04–3.20). High plasma neopterin level is an independent determinant of the risk of dementia in persons with Down syndrome. [Copyright &y& Elsevier]

Abstract: Objective: We investigated whether postpartum blues was related to changes in parameters of noradrenergic and serotonergic functioning. Methods: From 26 healthy pregnant women blood was collected at the end of pregnancy and 5 days and 6 weeks postpartum. Serotonergic parameters were: platelet serotonin content; paroxetine binding to platelet membranes as an index of serotonin transporter activity; the serotonin precursor tryptophan in proportion to the large neutral amino acids, as an estimate of its cerebral influx. Noradrenergic indices were the noradrenaline precursor tyrosine and its metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG). The Kennerly and Gath blues questionnaire was applied at day five postpartum. Results: The incidence of postpartum blues was 30%. The tryptophan ratio and serotonin content of platelets were decreased (p <0.01) at day five postpartum in all women. B max paroxetine at day five was correlated with blues score (ß =0.460; p =0.031). MHPG levels at 6 weeks were increased in women with blues (p <0.001). In a regression model MHPG at 6 weeks was related to blues score (ß =0.477; p =0.002) and MHPG at day five (ß =0.550; p =0.001), explaining >50% of the variation (R 2 =0.588; p <0.001). Conclusions: A decreased serotonergic activity was found at the fifth day postpartum in all subjects. Increased SERT activity, reflected by higher paroxetine binding to platelets might be involved in the onset of blues. The elevated MHPG levels in women with blues are compatible with a higher stress sensitivity, or a decreased stress coping in those and is suggested to be involved with the onset of depression. [Copyright &y& Elsevier]

Abstract: Tetrahydrobiopterin is a cofactor in the synthesis of monoamine neurotransmitters. High neopterin levels generally signal increased immune activation. Both pterins have been investigated in several small clinical studies of depressed patients with conflicting results. Therefore, we examined the relation of plasma biopterin and neopterin with depression in a population-based study. We also studied the association of pterins with folates in depressed persons as this vitamin is required for pterin biosynthesis. We screened 3884 adults aged 60 years and over for depressive symptoms. Screen positive subjects had a psychiatric interview to diagnose DSM-IV disorder. Plasma pterins and serum folate were determined in all persons with depressive symptoms (n =238) and randomly selected non-depressed persons (n =357). We found no association between the concentration of biopterin or neopterin with depressive symptoms or depressive disorders. However, in depressed persons the relation between pterins and folates was different than in the non-depressed, i.e. neopterin concentrations increased with folate levels in persons with depressive symptoms (0.09 per log(nmol/l folate); 95% CI=0.01, 0.18, P =0.03), but not in non-depressed persons (−0.07 per log(nmol/l folate); 95% CI=−0.17, 0.03, P =0.18). The interaction between depressive symptoms, folate and neopterin was significant (P =0.03). The study suggests that the relation between folate and pterins is altered in the depressed elderly. [Copyright &y& Elsevier]

The serotonergic system is believed to play a key role in the pathophysiology of seasonal affective disorder (SAD). Tetrahydrobiopterin is an essential cofactor in the hydroxylation of tryptophan and, therefore, in the synthesis of serotonin, while neopterin is known as a marker of cell-mediated immune activity. The present study was designed to measure levels of biopterin, neopterin and tryptophan in plasma of 19 depressed patients with a history of SAD, before and after light therapy as well as in a control group. In the group of patients a significantly lower plasma biopterin and tryptophan level and a higher neopterin level was demonstrated. After light therapy, the level of biopterin increased to that of the controls but lowered again in summer. Neopterin concentrations remained on the same level after light therapy, whereas tryptophan levels increased slightly after light therapy and reached normal values in summer. It is concluded that the vulnerability for a depressive episode is enhanced by lowered levels of biopterin that, however, in SAD becomes symptomatically manifest in the presence of increased immune activity at the same time. [Copyright &y& Elsevier]

Immunotherapy with interferon-alpha (IFN-α) induces neuropsychiatric side effects, most notably depression. One of the presumed pathophysiological mechanisms is an effect on tryptophan metabolism. As tryptophan is the precursor of serotonin, decreased availability of tryptophan to the central nervous system could result in serotonin deficiency. Tetrahydrobiopterin (BH(4)) is a cofactor for one of the enzymes synthesizing serotonin. We conducted an exploratory study into the serum concentrations of large neutral amino acids (AA), biopterin (BIOP) and neopterin (NEOP), of 67 patients with high-risk melanoma, who were either treated with two different doses of IFN-α or were part of an observation-only control group. We found evidence for IFN-α to decrease concentrations of all AA except phenylalanine. The decrease in tryptophan concentration was most prominent and consistent. These changes persisted throughout a year of maintenance treatment. Concentrations of NEOP rose sharply, whereas, those of BIOP did not change. Except for the increase in NEOP and the increase in the ratio between phenylalanine (PHE) and tyrosine (TYR), no support for derangement in BH(4) metabolism was found. The increase in the ratio between PHE and TYR suggests inhibition of the enzyme phenylalanine hydroxylase. Patients with IFN-α induced anxiety and depression had higher pretreatment concentrations of NEOP. Changes in tryptophan metabolism may play a role in the pathophysiology of the neuropsychiatric side effects of IFN-α, and further research into the predictive potential of NEOP is warranted. [Copyright &y& Elsevier]

Abstract: Objective: : To develop a reliable method for the determination of tetrahydrobiopterin and total biopterin in plasma. Methods: : Modifications include blood collection and handling procedures. Results: : Collection of blood in the presence of 0.1% (w/v) dithiothreitol and waiting for 2–3 h before centrifugation are optimal for adequate quantitation of both pterins. Conclusions: : For a reliable determination of tetrahydrobiopterin and total biopterin in plasma, blood tubes must contain a dimercapto-antioxidant and time between blood collection and centrifugation is critical. [Copyright &y& Elsevier]

Abstract: The efficacy of the addition of lithium to an established course of antidepressant treatment can be explained by a synergistic effect of the two drugs on central 5-HT neurotransmission. In the present study we investigated the effect of lithium addition on the 5-HT concentration in plasma and platelets and the concentration of 5-HIAA. Thirty-nine depressed inpatients who fulfilled the DSM-IV criteria for major depressive disorder and who did not respond to monotherapy with either imipramine or fluvoxamine participated in this study. Concentration of 5-HT in both plasma and platelets did not change significantly during lithium addition. The 5-HT ratio (plasma concentration/platelet concentration) shows a small non-significant increase after 3 weeks lithium addition. The mean concentration of 5-HIAA shows a significant increase during lithium addition; with no difference between the imipramine and the fluvoxamine sample. The increments in 5-HIAA concentration during lithium addition are indicative of an increased 5-HT turnover. [Copyright &y& Elsevier]

Abstract: Oxyresveratrol is a potent antioxidant and free-radical scavenger found in mulberry wood (Morus alba L.) with demonstrated protective effects against cerebral ischemia. We analyzed the neuroprotective ability of oxyresveratrol using an in vitro model of stretch-induced trauma in co-cultures of neurons and glia, or by exposing cultures to high levels of glutamate. Cultures were treated with 25μM, 50μM or 100μM oxyresveratrol at the time of injury. Trauma produced marked neuronal death when measured 24h post-injury, and oxyresveratrol significantly inhibited this death. Microscopic examination of glia suggested signs of toxicity in cultures treated with 100μM oxyresveratrol, as demonstrated by elevated S-100B protein release and a high proportion of cells with condensed nuclei. Cultures exposed to glutamate (100μM) for 24h exhibited ~37% neuronal loss, which was not inhibited by oxyresveratrol. These results show that the two pathologies of high glutamate exposure and trauma are differentially affected by oxyresveratrol treatment in vitro. Further studies using oxyresveratrol in trauma models are warranted, as toxicity to glia could be beneficial by inhibiting reactive gliosis, which often occurs after trauma. [Copyright &y& Elsevier]

Abstract: Background: Since there are few data on the possible association between BDNF levels and characteristics of major depression, the present study assesses brain-derived neurotrophic factor (BDNF) levels in three drug-free patient samples, and explores whether episode duration, and severity correlate with serum BDNF levels. Method: Serum BDNF levels were measured in 42 drug-free patients with major depression. The duration of the index episode and the presence of psychotic features were assessed with the Schedule for Affective Disorders and Schizophrenia, and the severity of depression was measured with the 17-item Hamilton Rating Scale for Depression. The sample was divided into three groups: severely depressed inpatients without psychotic features, severely depressed inpatients with psychotic features, and moderately depressed outpatients. Results: Mean serum BDNF level in the total sample was 18.0 ± 2.8 ng/ml, with no significant difference between the three patient samples (F = 1.80, df = 2, p = 0.18). Mean serum BDNF level was significantly lower in patients with an index episode over one year, compared with patients who had a shorter index episode (F = 4.90, df = 1, p = 0.033). Conclusion: These data show that patients with a long index episode have significantly lower serum BDNF levels. We found no influence of the presence of psychotic features and severity of depression on serum BDNF levels. [Copyright &y& Elsevier]

Summary: In generalized social anxiety disorder (gSAD), serotonergic dysfunctions are found, as well as abnormalities of the autonomic nervous system (ANS) in basal conditions and of the hypothalamic pituitary adrenal (HPA) axis in response to psychological challenges. These findings raise the question whether these phenomena are interrelated. Therefore we designed a study in which two groups with nine pair wise age and gender matched gSAD patients (total of 10 men and 8 women), who were successfully treated with a selective serotonin reuptake inhibitor (SSRI), underwent a tryptophan depletion challenge (TD) or a placebo condition. A TD procedure temporarily decreases serotonergic neurotransmission. In order to activate the stress system the TD/placebo challenge was combined with a public speaking task. We assessed ANS responses, as measured with the promising new marker salivary alpha-amylase (sAA), and HPA-axis responses, as measured with salivary cortisol. The most important result was that the TD group showed a significant larger sAA response to the public speaking task as compared to the placebo group, reflecting hyperresponsivity of the ANS in this group, whereas no differences were seen in cortisol responses. This suggests that in gSAD there is a vulnerability of the ANS more than the HPA-axis. [Copyright &y& Elsevier]

Abstract: Depression and cognitive disturbance are well-known neuropsychiatric side effects of therapy with interferon-alfa (IFN-alfa). Aggression and irritability are also reported as side effects. Probably, central nervous system (CNS) serotonergic dysfunction is one of the underlying pathophysiological mechanisms of IFN-alfa-induced neuropsychiatric toxicity. Platelet activity of monoamine oxidase-B (MAO; EC1.4.3.4) is a possible indicator of central serotonergic function. Moreover, low platelet MAO activity is linked to impulsiveness, addiction and personality disorder. In this exploratory study in 17 high-risk melanoma patients, platelet counts, whole blood MAO, and platelet MAO activity were measured before and during therapy with IFN-alfa. Patients were randomized to treatment either with pegylated IFN-alfa (PEG-IFN-alfa) once a week at a dose of 6 μg/kg/week subcuteanously (s.c.) during 8 weeks, followed by a maintenance treatment of 3 μg/kg/week s.c. for a total of 5 years, or to observation only. Blood samples were taken at baseline, 4 and 8 weeks and 3 months. During treatment with IFN-alfa, platelet counts decreased at 4 and 8 weeks and 3 months, while platelet MAO activity increased, both compared to baseline and compared to non-treated controls. Compared to non-treated controls, platelet MAO activity increased with 86.4% (95 CI: 52.9–127.2). No significant changes in platelet MAO activity were observed in the control group. This indicates that platelet MAO activity is influenced by IFN-alfa. Since platelet MAO activity is a model for CNS MAO-B activity, it may be speculated that CNS MAO-B activity will also be increased. This could influence serotonin (5-HT) metabolism and thereby contribute to the development of psychiatric disturbance. However, a preferential inhibition of platelet production cannot be ruled out. Hypothetically, the antiproliferative effects of IFN-alfa could interfere more strongly with the synthesis of platelets than with the synthesis of mitochondria. In that case, increased platelet MAO activity reflects an increased number of mitochondria per platelet. [Copyright &y& Elsevier]